Antibody drug conjugates (ADCs), a rapidly growing class of targeted therapeutics, represent a promising new approach toward improving both the selectivity and the cytotoxic activity of cancer drugs. Although several ADCs have demonstrated recent clinical success, the utility of most ADCs currently in development is limited by cumbersome synthetic processes, insufficient anti-tumor activity, and unpredictable toxicity. We believe that these drawbacks can be addressed by improvements in both linker technology and the cytotoxic drugs used to construct the ADCs. Our broad long-term goal is to develop novel ADCs with improved potency, homogeneity and stability over existing targeted therapeutics. Igenica has developed two proprietary technology platforms that provide a complementary function-oriented screening strategy to systematically identify novel tumor associated antigen targets and antigen-specific monoclonal antibodies for constructing ADCs with improved pharmacological properties. First, we have designed a novel bifunctional linker strategy that enables synthesis of ADCs with improved homogeneity and stability over conventional ADCs. These improvements will reduce the amount of cytotoxic drug payload that is released systemically and result in safer ADCs with longer half- lives in vivo. Additionally, we will utiliz tubulysins, a potent new class of anti-mitotic natural products, which are more potent than current ADC drug payloads. Our preliminary data indicates that tubulysins are up to 1000 times more potent than the currently utilized ADC payload, MMAF. Two specific aims are proposed. Aim 1) To demonstrate that novel bi-functional linkers can be used to construct homogeneous ADCs with improved stability. Aim 2) to demonstrate that tubulysins can be utilized to construct ADCs with improved potency. The Phase I milestones are designed to demonstrate the feasibility of using Igenica's innovative linkers and drug payloads by comparing ADCs that contain the clinically validated tumor specific antibody, Trastuzumab. In Phase II of this project we will combine the novel linkers and payloads described in Phase 1 and apply them to a novel tumor specific antibody. We will evaluate the resulting novel ADCs in relevant tumor models. If successful, these technologies will be applied to other antibodies in development for different indications and will ultimately have a significant impact on the fields of drug discovery and cancer therapeutics.